Circulation December 19/26, 2017 Issue

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Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

This week's journal features two papers. One a research letter and the second an original article, both focusing on the effect of ionizing radiation on interventional cardiologists. I'm sure that cuts close to the heart, so please stay tuned. Coming up right after these summaries.

The first two original articles in this week's journal describe a metabolic adaptation that is good for the abnormal cell but bad for the patient. This is a shift in glucose metabolism called the Warburg phenomenon where there is failure of two fundamental pathways. Number one glucose metabolism and number two mitochondrial oxygen sensing. This Warburg phenomenon enables a reliance on glycolysis despite an abundance of available oxygen. These two circulation articles uncover new players in the Warburg phenomenon, both in the setting of pulmonary arterial hypertension. One in the pulmonary arterial endothelial cells, and the second in fibroblasts.

In the first paper, first and corresponding author Dr. Caruso and co-corresponding author Dr. Morrell from the University of Cambridge examined the microRNA and proteomic profiles of blood outgrowth endothelial cells from patients with heritable pulmonary arterial hypertension due to mutations in the bone morphogenetic protein receptor type two, or BMPR2 gene, and in patients with idiopathic pulmonary arterial hypertension. They demonstrated that reduced expression of microRNA-124 in pulmonary arterial hypertension endothelial cells was responsible for the dysregulation of the splicing factor polypyrimidine tract binding protein 1, and its target pyruvate kinase M2 or PKM2, which is a major regulator of glycolysis and which contributes to abnormal cell proliferation. Reduced BMPR2 levels were associated with reduced microRNA-124 expression.

In the second paper first author Dr. Zhang, corresponding author Dr Stenmark and colleagues from the University of Colorado studied pulmonary adventitial fibroblasts isolated from cows and humans with severe pulmonary hypertension. PKM2 inhibition reversed the glycolytic status of pulmonary hypertension fibroblasts, decreased their cell proliferation and attenuated macrophage interleukin beta expression.

Normalizing the PKM2 to M1 ratio in pulmonary hypertension fibroblasts by using microRNA-124 over expression, or by PTBP1 knockdown, reversed the glycolytic phenotype, rescued mitochondrial reprogramming and decreased cell proliferation. Finally, pharmacological manipulation of PKM2 activity or treatment with histone deacetylase inhibitors produced similar results. These findings provide new avenues for the treatment of pulmonary arterial hypertension and are discussed in an accompanying editorial by Stephen Archer from Queen's University in Ontario Canada.

The next paper tells us that the addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. First and corresponding author Dr. Bohula and colleagues from the TIMI study group investigated the efficacy of the addition of ezetimibe to simvastatin for prevention of stroke in the IMPROVE-IT trial where post ACS patients were randomized to placebo and simvastatin or ezetimibe and simvastatin and followed for a median of six years.

The current study focused on patients with a history of stroke prior to randomization. The authors found that the addition of ezetimibe to simvastatin reduced the frequency of ischemic stroke with a hazards ratio of 0.79, with a particularly large effect seen in patients with a prior stroke, where the hazards ratio was 0.52, compared to patients without a prior stroke where the hazards ratio was 0.84. Hemorrhagic strokes were rare and a non significant increase in hemorrhagic stroke was observed with the addition of ezetimibe. Thus, the authors concluded that it is reasonable to consider the addition of ezetimibe, a generic lipid lowering therapy with an acceptable safety profile, to a moderate to high intensity statin regimen for the prevention of ischemic stroke in patients with established ischemic heart disease, with or without a prior stroke.

Atrial fibrillation is the most common sustained arrhythmia in hypertrophic cardiomyopathy, but the influence of atrial fibrillation on clinical course and outcomes in hypertrophic cardiomyopathy had remained incompletely resolved. That is until today's paper in circulation. First and corresponding author Dr. Rowin and colleagues from Tufts Medical Center accessed the records of 1,558 consecutive patients followed at the Tufts Medical Center hypertrophic cardiomyopathy institute for an average of 4.8 years from 2004 to 2014.

20% of patients had episodes of atrial fibrillation, of which 74% were confined to symptomatic paroxysmal atrial fibrillation, while 26% developed permanent atrial fibrillation. They found that the timing and frequency of paroxysmal atrial fibrillation events were unpredictable with an average two year interval between the first and second symptomatic episodes but progressing to permanent atrial fibrillation uncommonly. They further found that atrial fibrillation was not a major contributor to heart failure morbidity, nor a cause of arrhythmic sudden death, and when atrial fibrillation was treated it was associated with low disease related mortality, no different than for patients without atrial fibrillation. Finally, atrial fibrillation was an uncommon primary cause of death in hypertrophic cardiomyopathy, but this was virtually limited to embolic stroke, thus supporting a low threshold for initiating anticoagulation therapy.

That warps it up for our summaries. Now for our feature discussion. This week's journal carries two papers that refer to the health risks of ionizing radiation to interventional cardiologists. Yes, you heard me right. You're going to want to listen up. These are going to send chills up our spine, or rather maybe chills into our brains and into our blood according to the papers.

To discuss these two papers I have with us associate editor from UT Southwestern, Dr. Manos Brilakis, as well as the corresponding author of the first paper Dr. Maria Andreassi from CNR Institute of Clinical Physiology from Pisa Italy. Maria, could you start us off by telling us what you found in your research letter?

Dr Maria Andreassi: In our study we evaluated the circulating microRNA profile in interventional cardiologists in order to provide insights into the molecular and the biological situation and the underlying association between occupational low dose radiation exposure in cath lab and the potential long term disease risk. The hypothesis of our study was based on the evidence that the microRNAs are crucial regulators of gene expression. And they have been shown to be dysregulated in many human disease. Moreover, the stability and the tissue selectivity of circulating microRNAs make them ideal biomarkers to explore disease potential clinical disease risk.

In summary, our findings exhibited the dysregulation and the down regulation of acute specific circulating microRNA, the brain specific microRNA-154 and the microRNA-2392. This tells us significantly involved in the deregulation of the three brain pathways and the brain cancer pathway as demonstrated by systematic analysis. In particular, the dysregulated labels so the brain specific microRNA-154 in interventional cardiologists support the notion that the brain damage is one of the main potential long term risk on unprotected head radiation in interventional cardiologists with possible long lasting consequences on the cognitive function.

Dr Carolyn Lam: That is really striking. Brain specific microRNA was shown to be dysregulated in interventional cardiologists compared to controls who were not exposed to radiation. As I understand it, these dysregulated microRNAs can be seen in certain forms of epilepsy and Alzheimer's disease and certain brain cancers and so the concern is very obvious for those of us who are interventional cardiologists. But your study did not actually relate these two specific adverse events. Is that correct?

Dr Maria Andreassi: You're right. Yes. microRNA-154 was first identified as a brain specific microRNA which is involved with inner synapse development and the directly implicated in [inaudible 00:12:15] and memory. Additionally, decreased expression of this microRNA class, was previously reported in several brain disorders including the thymus disease and bipolar disorder. This microRNA has also been shown to be down regulated in several brain cancers such as neuroblastomas. The reduced expression of the microRNA-154 is a predictor of progression and prognosis of human gliomas. This data strongly support it's important role in brain tumors. Our findings are of particular interest in relation the handle exposure to the pathology of the head, the [inaudible 00:13:13] 20, 50 millisieverts. The equivalent to 1,000, 2,000 chest x-rays and can reach a lifetime cumulative exposure around two sieverts for left hippocampus and one sievert for right hippocampus.

Dr Carolyn Lam: That really makes me go, yikes. But Manos, as an interventional cardiologist yourself, what are your thoughts? And also your thoughts please on that other paper that's in this week's journal?

Dr Manos Brilakis: First of all, let me just congratulate Maria Andreassi, she's been one of the leaders in this area and published several papers and this is one of them. It's really important to have these studies because unfortunately we as interventional cardiologists tend to forget about the negative affects of radiation because as you hear, people don't really see them and this can happen many years down the line. And by the time they happen, it's too late. It's really useful to have the studies to bring our attention the importance of keeping the radiation exposure to the patient and to ourselves as low as possible.

The other paper in addition to the one just discussed, is a paper that looks at DNA damage on operators performing endovascular aortic repair. As a preface, these are procedures demonstrated the aortic aneurism repairs which are very intense radiation wise. They are long procedures, fielding can sometimes be challenging for the operator. There is significant exposure of the operator to x-ray. What they did is they measured some markers of DNA damage and repair. Specifically gamma-H1AX and DDR, the DNA damage response marker and the pATM. They measured them in circulating lymphocytes in operators who performed the endovascular aortic aneurism. What they found is that there were significantly higher levels of those markers immediately after those operators performed those procedures. And they did the same thing after x-ray using leg shielding.

That's a very good reminder for us that the x-ray tube actually is not on the top of the table, but the x-ray tube, the generator, of the x-rays is actually on the bottom. Then the x-ray goes through the patient and the detector is at the top of the table and what happens is the x-ray comes from below the patient and gets scattered from the patient and coming towards the operator so actually it's the legs get the higher dose during any sort of x-ray guided procedure. Sometimes we're forgetting importance of shielding the legs 'cause we think the legs, whatever the muscles, the bones, they're fine. But as the study shows, it's not just the muscles and the bones there but the whole circulation blood gets exposed to x-ray in the lower extremity circulation and that can translate to many other potentially adverse events.

Dr Carolyn Lam: Manos, I love that you manage both these papers. What important messages for increase in risk awareness. This was really very, very well accomplished by both these papers. As well by the editorial that you asked for and that was so well written by Dr. Charles Chambers on both these papers. But beyond risk awareness, what I really love is what you brought up just a while earlier about risk reduction and methods that we can take, for example, in the second paper, by Dr. Modoari and colleagues about shielding the legs. What are the implications for example, wearing a helmet or shielding the head for interventional cardiologists? What do you think?

Dr Manos Brilakis: These are very, very good points. The reality is for the head there have been a couple studied that looked at shielding with lead caps or there's some lead free caps that can be worn and also there are radiation protective glasses. However, what was interesting, there was a paper earlier last year that showed that because the radiation actually comes from below the operator that wearing those helmets, although it seems appealing, it is simple to do obviously, it actually did not significantly reduce the dose to the brain and it only partially reduced the dose to the eyes. Though shielding is useful but may not be as good as we think it is.

In my mind, the starting point of all this is the basics of radiation safety which again, sound very simple and we learn about them in the beginning of training, unfortunately what happen is people tend to forget them as time goes by. These are things like don't step on the x-ray pedal unless you need to look at the pictures and that's very common done. People just have this heavy foot syndrome. They keep on x-raying when they don't need to. There's also the important things having the patient as high as possible and the detector as close to the patient so there is not as much distance for the x-ray to travel. Things like using low, not very steep angles so there is not as much radiation because they have to go through less amount of tissue. And there's some technologies actually coming along there's some technologies that focus the radiation beam only specific areas. And cut the overall dose. And there are x-ray machines that also can have much less radiation overall for the patient and the operator. As you said, having good shielding habits is very important.

Dr Carolyn Lam: Yeah, that's exactly it. That risk awareness should lead to action. I'm just curious, who do you think should primarily take hold of these risk reduction and safety procedures and the enforcement and so on? Us as a community, but what do you think of the role of things like professional societies, quality improvement programs, FDA even?

Dr Manos Brilakis: It's a great point. What we hear here Maria's comments on this as well. But my feeling is absolutely societies are very important for leading these efforts and they do have actually guidelines. There's procedural guidelines for radiation protection. But the end of the day it's the individuals themselves, the operators, each and every one who is in charge of this in their care or his own cath lab and their procedures.

Dr Maria Andreassi: I agree. We all of our findings can contribute to the increase of cross cultural assessment in cath lab and by promoting the diffusion but not the reduction technologies whereas diligent about your protection habits. Moreover it is important to let the design, the relationship between occupational radiation exposure, clinical risk and there are very important future studies studying larger population. We should focus on the molecular epidemiology studies by using biomarkers and this will be clinical and points as early predictors of a clinical event. Because this information is a model likely to better define the risk of radiation use disease at low doses as a comparative tool, the classical epidemiological approach that require a very large sample sizes spread over [inaudible 00:20:51].

Now it's time where largest studies involving scientific societies at an international level. Possible breaking the additional exposure in already recruited the Roth case. And by combining the conventional epidemiology, and the molecular studies and the expected results to better define the clinical risk as a good lesson to implement a more effective protection program. And better as the surveillance at the individual level.

Dr Carolyn Lam: That is wonderful. And thank you, this truly is an international call, isn't it? Another thing that we should keep in mind that all measures that we use to protect our patient from receiving excessive radiation is likely to help us as well as cardiologists.

Thank you so much, both of you, for joining me today on this podcast. What an important message and I'm sure that our listeners will agree. Thank you listeners for joining us. Tune in again next week.

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